NM_001330260.2:c.1999-5delT

Variant names:

• chr12-51745885-CT-C
• rs769940455
• NM_001330260.2:c.1999-5delT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_001330260.2(SCN8A):​c.1999-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 957,358 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene SCN8A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 31)
  • Exomes 𝑓: 0.17 (0 hom.)
• Consequence: SCN8A NM_001330260.2 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.316
• Publications: 0 publications found

Genes affected

SCN8A (HGNC:10596): (sodium voltage-gated channel alpha subunit 8) This gene encodes a member of the sodium channel alpha subunit gene family. The encoded protein forms the ion pore region of the voltage-gated sodium channel. This protein is essential for the rapid membrane depolarization that occurs during the formation of the action potential in excitable neurons. Mutations in this gene are associated with cognitive disability, pancerebellar atrophy and ataxia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

SCN8A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia
• developmental and epileptic encephalopathy, 13

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• cognitive impairment with or without cerebellar ataxia

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• seizures, benign familial infantile, 5

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• benign familial infantile epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile convulsions and choreoathetosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myoclonus, familial, 2

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Specifications for SCN8A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 12-51745885-CT-C is Benign according to our data. Variant chr12-51745885-CT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212134.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330260.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN8A	NM_001330260.2	MANE Select	c.1999-5delT		splice_region intron	N/A	NP_001317189.1	Q9UQD0-2
	SCN8A	NM_014191.4	MANE Plus Clinical	c.1999-5delT		splice_region intron	N/A	NP_055006.1	Q9UQD0-1
	SCN8A	NM_001177984.3		c.1999-5delT		splice_region intron	N/A	NP_001171455.1	Q9UQD0-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN8A	ENST00000354534.11	TSL:1 MANE Plus Clinical	c.1999-17delT		intron	N/A	ENSP00000346534.4	Q9UQD0-1
	SCN8A	ENST00000627620.5	TSL:5 MANE Select	c.1999-17delT		intron	N/A	ENSP00000487583.2	Q9UQD0-2
	SCN8A	ENST00000599343.5	TSL:5	c.2032-17delT		intron	N/A	ENSP00000476447.3	Q9UQD0-3

Frequencies

GnomAD3 genomes AF: 0.00348 AC: 496 AN: 142350 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00177

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00286

Gnomad ASJ AF: 0.00182

Gnomad EAS AF: 0.000402

Gnomad SAS AF: 0.000224

Gnomad FIN AF: 0.0144

Gnomad MID AF: 0.00342

Gnomad NFE AF: 0.00376

Gnomad OTH AF: 0.00465

GnomAD2 exomes AF: 0.244 AC: 19513 AN: 80108 AF XY: 0.258

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.290

Gnomad ASJ exome AF: 0.313

Gnomad EAS exome AF: 0.241

Gnomad FIN exome AF: 0.201

Gnomad NFE exome AF: 0.228

Gnomad OTH exome AF: 0.267

GnomAD4 exome AF: 0.174 AC: 141659 AN: 814970 Hom.: 0 Cov.: 0 AF XY: 0.175 AC XY: 71493 AN XY: 407610

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.170 AC: 3086 AN: 18192

American (AMR) AF: 0.190 AC: 4025 AN: 21236

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 2856 AN: 14322

East Asian (EAS) AF: 0.189 AC: 4482 AN: 23662

South Asian (SAS) AF: 0.192 AC: 9883 AN: 51418

European-Finnish (FIN) AF: 0.181 AC: 5722 AN: 31682

Middle Eastern (MID) AF: 0.103 AC: 392 AN: 3822

European-Non Finnish (NFE) AF: 0.170 AC: 104977 AN: 616692

Other (OTH) AF: 0.184 AC: 6236 AN: 33944

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00350 AC: 498 AN: 142388 Hom.: 1 Cov.: 31 AF XY: 0.00377 AC XY: 261 AN XY: 69154

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00179 AC: 70 AN: 39124

American (AMR) AF: 0.00286 AC: 41 AN: 14322

Ashkenazi Jewish (ASJ) AF: 0.00182 AC: 6 AN: 3298

East Asian (EAS) AF: 0.000403 AC: 2 AN: 4960

South Asian (SAS) AF: 0.000450 AC: 2 AN: 4448

European-Finnish (FIN) AF: 0.0144 AC: 125 AN: 8710

Middle Eastern (MID) AF: 0.00373 AC: 1 AN: 268

European-Non Finnish (NFE) AF: 0.00376 AC: 242 AN: 64418

Other (OTH) AF: 0.00461 AC: 9 AN: 1952

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00992 Hom.: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs769940455; hg19: chr12-52139669; COSMIC: COSV61978474; COSMIC: COSV61978474;